Nonadjuvanted Bivalent Respiratory Syncytial Virus Vaccination and Perinatal Outcomes

Key Points Question Is there an association between nonadjuvanted bivalent respiratory syncytial virus prefusion F (RSVpreF) protein subunit vaccination during pregnancy and preterm birth? Findings In this cohort study of 2973 patients who delivered during the 2023 to 2024 recommended vaccination period, 34.5% had evidence of prenatal RSVpreF vaccination. There was no increased risk of preterm birth based on maternal vaccination status. Meaning These clinical vaccine data add to the existing evidence from trials supporting the safety of prenatal RSVpreF vaccination.


Introduction
6][7] For the 2023 to 2024 RSV season, the limited supply of nirsevimab 8 made prenatal vaccination more important.
On September 22, 2023, the US Centers for Disease Control and Prevention (CDC)'s Advisory Committee on Immunization Practices recommended the RSVpreF vaccine to be administered to most pregnant individuals from September to January in the continental United States. 9This is in contrast to the RSV adjuvanted vaccine (GlaxoSmithKline), which is not approved for use in pregnant individuals based on a trial that was terminated early due to an elevated risk of premature birth and associated neonatal deaths. 10Although the RSVpreF vaccine was approved by the FDA, 11 the gestational age window was limited to 32 0/7 to 36 6/7 weeks due to concerns raised about the numerical difference seen in preterm birth (PTB) among participants who received the RSVpreF vaccine from 24 to 36 weeks' gestation.Of note, the imbalance was only seen in participants residing in low-to middle-income countries. 4e recommendation that most pregnant individuals, with few exclusions, should receive the RSVpreF vaccine between 32 0/7 and 36 6/7 weeks' gestation was endorsed by major US obstetric care professional organizations. 12,13However, clinical data from the US 2023 to 2024 RSV season are currently lacking.Therefore, we aimed to examine the uptake of RSVpreF vaccination among a medically and demographically diverse pregnant population during the 2023 to 2024 RSV season and compare those who were prenatally vaccinated with those who were not.

Methods
This is a retrospective observational cohort study of patients who delivered at 32 0/7 weeks' gestation or later at 2 New York City (NYC) hospitals within 1 health care system from September 22, 2023, to January 31, 2024.We chose this gestational age threshold to include patients who had an opportunity to be exposed.Patients with unknown gestational ages and those with multifetal gestations were excluded.Data were extracted directly from a research data repository populated with structured data from the electronic health record (EHR).This repository is updated on a regular basis with a 1-week lag time and captures standardized and templated fields, including recorded diagnoses (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM]) and billing codes (Current Procedural Terminology and Healthcare Common Procedure Coding System) as well as data on visits, medications, and laboratory and imaging results.The repository leverages existing institutional infrastructure 14 and is subject to rigorous quality assurance checks by informatics personnel and clinical staff.Data were extracted using direct structured query language queries against the repository by 2 of us (S.Y. and E.S.) and validated by 2 of us (M.S. and A.P.S.).The EHR links birthing parent and infant records in the obstetric module (Epic STORK).Demographic information such as race and ethnicity were extracted from the demographic fields, which are typically captured by self-report during visit encounters.Race and ethnicity were collected because the burden of RSV illness 15 and the likelihood of vaccination 16,17 are disproportionate among different racial and ethnic groups.Estimated delivery date (EDD) and gestational age were identified through templated fields; it is institutional practice to enter the EDD in the EHR using the best available clinical estimation. 18This study was approved by the Weill Cornell Medicine institutional review board with a waiver of informed consent due to it having public health benefit, posing minimal risk to patients, not being practical to carry out without a waiver, and not adversely affecting the rights and welfare of participants due to its retrospective nature.We report our findings following the and it was identified via the prescription method.

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The primary outcome was PTB, defined as any birth occurring at less than 37 weeks' gestation.
We determined whether the PTB was spontaneous (birth after preterm labor or preterm premature rupture of membranes) or nonspontaneous using available labor and birth data in the repository (eMethods in Supplement 1).Secondary pregnancy outcomes were hypertensive disorders of pregnancy (HDP), small-for-gestational age (SGA) birth weight, and stillbirth.Secondary neonatal outcomes were neonatal intensive care unit (NICU) admission, respiratory distress with NICU admission, jaundice or hyperbilirubinemia, hypoglycemia, and sepsis.HDP was inclusive of gestational hypertension; preeclampsia; eclampsia; and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome.The diagnoses of HDP, neonatal respiratory distress, neonatal jaundice or hyperbilirubinemia, neonatal hypoglycemia, and neonatal sepsis were based on ICD-10-CM codes and cross-checked for data quality with other data available in the repository (eTable 1 in Supplement 1).Stillbirth was based on ICD-10-CM codes (eTable 1 in Supplement 1) and total Apgar score of 0 at 1 minute of life.SGA was defined as birth weight in less than the 10th percentile and based on gestational age at birth and neonatal sex using established thresholds. 20,21Aside from birth weight, all neonatal outcomes were assessed for occurrence within 5 days of life.Only cases of neonatal respiratory distress that occurred with NICU admission were included to avoid mild cases requiring only initial resuscitation.

Statistical Analysis
Descriptive statistics were performed using median and IQR for continuous variables, given the nonparametric distributions, and using frequency and percentage for categorical variables.To evaluate whether baseline characteristics were associated with vaccine exposure, bivariate analyses were performed using Wilcoxon rank sum tests for continuous variables and χ 2 and Fisher exact tests, as appropriate, for categorical variables.Complete case analyses were performed.The falsediscovery rate method was used to account for multiple comparisons, and an analog q value of .05 was set as the threshold for statistical significance.
We used 3 stepwise approaches to evaluate associations between vaccination and pregnancy outcomes (PTB, HDP, and SGA).First, we ignored all potential biases (naive approach) and used logistic regression models to estimate the associations.Second, multivariable analyses were

JAMA Network Open | Infectious Diseases
Nonadjuvanted Bivalent RSV Vaccination and Perinatal Outcomes performed, and covariates were chosen based on whether they were statistically significant (q < .05) in bivariate analyses or thought to be potential clinical confounders.Third, in addition to step 2, we accounted for time-dependent vaccine exposure within pregnancy (immortal time bias) using timedependent covariate Cox regression models.Measures of association are presented with 95% CIs.
For the stillbirth outcome, adjusted analyses were not performed given the small number of cases.
Two stratified analyses were performed for the pregnancy outcomes (PTB, HDP, and SGA).The first was based on insurance type (Medicaid/Medicare vs private) and the second on hospital site (Weill Cornell Medical Center vs Lower Manhattan Hospital).
For neonatal outcomes, logistic regression models were performed, and odds ratios (ORs) and 95% CIs were calculated.Stratified analyses were performed based on gestational age at birth (<35 vs Ն35 weeks' gestation) since this is the institutional threshold for automatic NICU admission and could have affected neonatal outcomes.
Two sensitivity analyses were performed to determine the robustness of our results.First, we excluded all patients who had fewer than 2 prenatal care visit encounters at hospital-affiliated clinical sites, as they likely did not have adequate opportunity to be exposed to vaccination or have documentation of vaccination prenatally.Second, we excluded patients who had an EDD after the study period end (January 31, 2024) to ensure complete gestations for the assessment of pregnancy outcomes.
Given our sample size, a post hoc power analysis suggested that the study had 80% power to detect an absolute risk reduction of 2.6% or greater in the primary outcome of PTB, using a Fisher  2).In stratified analyses, there were differences noted for risks of HDP and SGA based on insurance type and hospital site (eTables 2-4 in Supplement 1).Sensitivity analyses did not reveal additional findings (eTables 5 and 6 in Supplement 1).
Among offspring, there were no significant differences in outcomes (Table 3).In the stratified analyses based on less than 35 weeks' gestation vs 35 weeks' gestation or longer at birth (eTable 7 in Supplement 1) and sensitivity analyses (eTables 5 and 6 in Supplement 1), we found similar nonsignificant findings.

Discussion
At our 2 hospitals, 34.5% of individuals who delivered during the 2023 to 2024 RSV vaccination season had documented evidence of prenatal RSVpreF vaccination.RSVpreF vaccination steadily increased throughout the 2023 to 2024 RSV season, with the largest increase seen after on-site vaccine availability.In the main analyses, there were no significant differences in maternal or perinatal outcomes between patients who had EHR evidence of prenatal RSVpreF vaccination and those who did not.However, there were increased risks of HDP and SGA birth weight seen when accounting for immortal time bias, hospital site, and insurance type.
The vaccine uptake among our patients is higher than what has been reported nationally.In contrast to our vaccination frequency of 34.5%, the CDC reports the overall coverage with the RSV vaccine nationally was 17.8% during the same time period. 22While the sociodemographic profile of our patient population (majority self-identified as non-Hispanic, White, or Asian with private insurance) may reflect people more likely to receive vaccination, we believe that our hospitals' early efforts to optimize equitable vaccination access by stocking and administering the vaccine in most clinical sites promoted vaccination among our patients.Indeed, receipt of RSVpreF vaccine increased most substantially after on-site vaccine availability.
The CDC report showed that RSVpreF vaccination coverage was highest among non-Hispanic Asian (24.8%) and lowest among non-Hispanic Black (10.3%) pregnant individuals. 22Our study similarly found significant differences in the distribution of self-identified race and ethnicity based on vaccination status.We found a significantly lower vaccination frequency among patients who selfidentified as Black or Hispanic and those with government insurance.It is well recognized that for other recommended prenatal vaccines such influenza, COVID-19, and tetanus-diphtheria-pertussis, vaccination rates are significantly lower in non-Hispanic Black or African American and Hispanic or Latina pregnant individuals compared with their non-Hispanic White counterparts. 23 during pregnancy, lack of access, cost, and patient preference for nirsevimab for their infant.
We did not find a significant difference in overall PTB at less than 37 weeks' gestation between our study groups.In contrast to the trials, 4 which observed more cases of PTB at less than 37 weeks' gestation among RSVpreF vaccine recipients than among placebo recipients (although not statistically significant), we observed fewer cases of PTB among our patients with EHR evidence of vaccination compared with those without.It is possible that we found a different trend because our study was performed in the postmarket period when the vaccine was recommended to be administered in the window of 32 0/7 to 36 6/7 weeks' gestation (compared with the 24 0/7 to 36 6/7 weeks' gestation window used in the trials 4 ).However, it is notable that, even in the trial, 4 the trend was driven by imbalances in PTB in low-and middle-income countries.In their analysis of US births only, the PTB rate was 5.1% (126 of 2494) in the vaccine group compared with 5.1% (126 of 2484) in the control group. 4Additionally, the original analysis 4 of US participants enrolled during the approved dosing interval (32 0/7 to 36 6/7 weeks' gestation) demonstrated that the imbalance was reversed, with PTBs occurring in 4.0% (721 of 1628) in the vaccine group compared with 4.4% (732 of 1604) in the control group.Our study shows a similarly reassuring trend for PTB.While our overall frequency of PTB is higher than the trial, this is likely because we did not limit our cohort to healthy individuals, as was done in the trial 4 (ie, exclusion of patients with endocrine disorders, in vitro fertilization, and prior or current pregnancy complications).
In the time-dependent model only, we found a significantly increased risk of overall HDP in the vaccinated group.The trial 4 also observed more cases of gestational hypertension and preeclampsia among RSVpreF vaccine recipients than among placebo recipients, although these associations were not statistically significant.In our stratified analyses, the significantly increased risks of HDP appeared to be associated with insurance type and hospital site.These findings should be investigated in other populations and settings.In our main analyses, we did not find significant differences overall in SGA, stillbirth, or other neonatal outcomes, such as NICU admission, respiratory distress, hypoglycemia, jaundice or hyperbilirubinemia, or sepsis, between the 2 groups.

Strengths and Limitations
Our study has several strengths.First, it provides clinical data for the first RSV season in the continental US during the postmarket period of an FDA-approved and nationally recommended RSV vaccine specific to the pregnant population.Second, we had a higher proportion of vaccinated patients compared with nationally reported estimates, 22 which allowed us to make important  comparisons.Third, we included most patients who delivered at our 2 hospitals, which expands on the trial population, 4 which included only patients with low risk.Fourth, we explored important neonatal outcomes not previously reported in the trial. 4Fifth, we utilized several statistical approaches to minimize potential biases that commonly affect postmarket observational vaccine studies. 24,25ere are notable limitations.First, our patient population and our NYC location may not be generalizable to other settings.Second, RSVpreF vaccination status was based on EHR documentation.Although we utilized multiple channels to comprehensively capture immunization data, we may not have captured vaccinations performed at smaller non-PBM-owned pharmacies or clinical sites not part of the EHR.Therefore, it is possible that some patients were misclassified as not having received vaccination when they in fact did, potentially biasing results toward the null.
Third, there may be a residual risk of immortal time bias 26

Conclusions
In this cohort study of pregnant individuals who delivered at 32 weeks of gestation or later at 2 NYC hospitals, EHR evidence of prenatal RSVpreF vaccination was not associated with PTB.These data add to the existing evidence supporting the overall safety of prenatal RSVpreF vaccination.However, there may be increased risks of HDP and SGA when addressing immortal time bias, hospital site, and insurance type, and these associations should be investigated further.Additionally, prenatal RSVpreF vaccination remains underutilized, and exploration of the factors and disparities associated with prenatal vaccination is needed.

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The vaccinated group on average was older and more likely to be nulliparous, have private insurance, and have a pregnancy by in vitro fertilization.The vaccinated group was less likely to have a diagnosis of pregestational diabetes and an admission body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or greater.There were significant differences in the distribution of self-identified race and ethnicity and delivery hospital site between groups.
exact test with a .052-sidedsignificancelevel(assumingabaselinePTBproportion of 6.7% in the nonvaccinated group).R software version 4.2.3 (R Foundation for Statistical Computing) was used for statistical analyses.ResultsBetweenSeptember 22, 2023, and January 31, 2024, 2973 eligible pregnant individuals (median [IQR] age, 34.9 [32.4-37.7]years,618[20.8%]Asian;194[6.5%]Black or African American; 295 [9.9%] Hispanic, Latino, or Spanish origin; 1687 [56.7%]White; and 248 (8.3%) with other race and ethnicity, including American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander)were included after excluding 53 patients for unknown gestational age and 42 for multifetal gestations.These patients delivered at our 2 hospitals at 32 0/7 weeks' gestation or later.Among them, 1026 (34.5%) had EHR evidence of RSVpreF vaccination before delivery, and 1947 (65.5%) did not.The mean (SD) gestational age at time of vaccination was 34.5 (1.4) weeks.The frequency of vaccination increased steadily, with the steepest increase after the availability of on-site vaccination(Figure).The baseline characteristics of patients with and without EHR evidence of prenatal RSVpreF vaccination are shown in Table1

Table 1 .
Characteristics of Patients Who Had RSV Vaccination During Pregnancy Documented in Their Electronic Health Record vs Those Who Did Not d Data are available for 854 patients who had evidence of vaccination and 1564 patients who did not have evidence of vaccination.eData are available for 1007 patients who had evidence of vaccination and 1918 patients who did not have evidence of vaccination.

Table 2 .
16,17ancy Outcomes Between Patients Who Had RSV Vaccination During Pregnancy Documented in Their Electronic Health Record vs Those Who Did Not Small for gestational age determined based on gestational age (in weeks) at birth and sex using the Fenton reference.16,17 d

Table 3 .
Secondary Neonatal Outcomes Between Offspring Born to Patients Who Had Documentation of Receiving RSV Vaccine During Pregnancy vs Those Born to Patients Who Did Not JAMA Network Open.2024;7(7):e2419268.doi:10.1001/jamanetworkopen.2024.19268(Reprinted) July 8, 2024 7/10 Downloaded from jamanetwork.comby guest on 07/11/2024 22r outcomes like PTB, since the modified vaccination window recommended made it more likely to be administered at gestations near full term (ie, close to 37 weeks' gestation).Fourth, several outcome variables, including HDP, neonatal respiratory distress, neonatal hypoglycemia, and neonatal hyperbilirubinemia or jaundice, were based on ICD-10-CM codes and not individually confirmed.However, we sought to maximize data validity by cross-checking them with clinical data.Fifth, we had a higher vaccination frequency than what is nationally estimated,22and our PTB risk trended opposite to what was previously suggested; however, our sample size may still be underpowered, and the risk of type II error persists.
Fell DB, Dimitris MC, Hutcheon JA, et al.Guidance for design and analysis of observational studies of fetal and newborn outcomes following COVID-19 vaccination during pregnancy.Vaccine.2021;39(14):1882-1886.doi:10.1016/j.vaccine.2021.02.070 26.Yadav K, Lewis RJ. Immortal time bias in observational studies.JAMA.2021;325(7):686-687. doi:10.1001/jama.2020.9151Hierarchical Logic for Determination of Spontaneous vs Nonspontaneous Indication for Delivery Based on Available Labor and Delivery Data in Repository eTable 1.International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Codes Used for Data Variables eTable 2. Stratified Analyses for the Association Between Respiratory Syncytial Virus Vaccination and the Risks of Preterm Birth at Less Than 37 Weeks of Gestation by Maternal Insurance Type and Delivery Hospital Site eTable 3. Stratified Analyses for the Association Between Respiratory Syncytial Virus Vaccination and the Risks of Hypertensive Disorders of Pregnancy by Maternal Insurance Type and Delivery Hospital Site eTable 4. Stratified Analyses for the Association Between Respiratory Syncytial Virus Vaccination and the Risks of Small for Gestational Age Birthweight by Maternal Insurance Type and Delivery Hospital Site eTable 5. Sensitivity Analyses for the Association Between Maternal Respiratory Syncytial Virus Vaccination and Pregnancy Outcomes Among Mother-Infant Dyads with Evidence of Prenatal Care at Hospital-Affiliated Clinics During Pregnancy eTable 6. Sensitivity Analyses for the Association Between Maternal Respiratory Syncytial Virus Vaccination and Pregnancy Outcomes Among Patients with Estimated Due Dates On or Before January 31, 2024 eTable 7. Stratified Analyses for the Association Between Respiratory Syncytial Virus Vaccination and the Risks of Adverse Neonatal Outcomes by Gestational Age at Birth 25.